RESEARCH ARTICLE Open Access
Analysis o bea ing wea , whole blood and
syno ial luid me al ion concen a ions and
his opa hological indings in pa ien s wi h
ailed ASR hip esu acings
La i Leh o i a
1,2*
, Aleksi Rei o
2
, Jy ki Pa kkinen
3
, Ha y Ho hi
4
, Johann Henckel
4
, Alis e Ha
4
and An i Eskelinen
2
Abs ac
Backg ound: Ad e se Reac ion o Me al Deb is (ARMD) is s ill a majo eason o e ision su ge ies in pa ien s wi h
me al-on-me al (MoM) hip eplacemen s. ARMD consis s o a wide ange o al e a ions in pe ip os he ic issues, mos
impo an o which a e me allosis, in lamma ion, pseudo umo s and nec osis. S udies in es iga ing his opa hological
indings and hei associa ion o implan wea o indi ec measu es o wea ha e yielded inconsis en esul s. The e o e,
we aimed o in es iga e bea ing su ace wea olume, whole blood and syno ial luid me al ion concen a ions,
his opa hological indings in pe ip os he ic issues and hei associa ions.
Me hods: Se en y-eigh pa ien s wi h 85 hips e ised o ARMD we e included in he s udy. P io o e ision su ge y,
all pa ien s had whole blood ch omium and cobal ion le els assessed. In e ision su ge y, a syno ial luid sample was
aken and analyzed o ch omium and cobal . Pe ip os he ic issue samples we e aken and analyzed o his opa hological
indings. Explan ed implan s we e analyzed o bea ing wea olume o bo h ace abula cup and emo al head
componen s.
Resul s: Volume ic wea o he ailed componen s was highly a iable. The o al wea olume o he head and cup had
a s ong co ela ion wi h whole blood ch omium and cobal ion concen a ions (C : ρ=0.80,p<0.001andCo:ρ=0.
84, p< 0.001) and a bi weake co ela ion wi h luid ch omium and cobal ion concen a ions (C : ρ=0.50,p<0.01and
Co: ρ=0.41,p= 0.027). Mos issues displayed only low- o-mode a e amoun s o mac ophages and lymphocy es. To al
wea olume co ela ed wi h mac ophage shee hickness (ρ=0.25,p= 0.020) and nec osis (ρ=0.35,p<0.01).Whole
blood ch omium and cobal ion concen a ions had simila co ela ions. Lymphocy e cu hickness did no co ela e
wi h ei he o al wea olume o whole blood me al ion concen a ions, bu co ela ed wi h he g ade o nec osis.
Conclusions: Bea ing wea olume co ela ed wi h blood me al ion le els and he deg ee o nec osis and
mac ophage in il a ion in pe ip os he ic issues sugges ing a dose- esponse ela ionship. Whole blood me al ion le els
a e a use ul ool o clinician o es ima e bea ing wea and subsequen issue esponse.
Keywo ds: Me al-on-me al hip eplacemen , Ad e se eac ion o me al deb is, ARMD, ALTR, ALVAL, Wea ,
His opa hology
* Co espondence: [email p o ec ed]
1
Facul y o Medicine, Uni e si y o Tampe e, Tampe e, Finland
2
Coxa Hospi al o Join Replacemen , Tampe e, Finland
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Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523
DOI 10.1186/s12891-017-1894-5
Backg ound
Ad e se eac ion o me al deb is (ARMD) is s ill a
majo eason o e ision su ge ies in pa ien s wi h
me al-on-me al (MoM) hip implan s. Al hough he
use o MoM hip implan s has been widely ceased,
mo e han one million pa ien s ha e ecei ed such a
de ice [1] and hose ha ha e no been e ised s ill
pose an inc eased isk o implan ailu e. ARMD is
an umb ella e m desc ibing a wide ange o al e -
a ions seen mac o- and mic oscopically in he pe i-
p os he ic issue such as me allosis, nec osis,
in lamma ion o di e en ypes and so - issue in lam-
ma o y lesions e e ed as pseudo umo s [2–4].
Re ie al s udies ha e in es iga ed implan wea and
i s associa ion o ARMD. Resul s o hese s udies ha e
been inconclusi e as ad e se eac ions ha e been ob-
se ed bo h in pa ien s wi h high and low wea ing hip
implan s [5–11]. In hei ecen sys ema ic e iew,
Campbell e al. concluded ha no clea dose- esponse
ela ionship be ween wea and ARMD could be es ab-
lished due o he he e ogenei y o he indings in he in-
cluded s udies. S udies ha ha e in es iga ed wea o
indi ec ma ke s o wea , such as syno ial luid (SF) o
whole blood (WB) me al ion concen a ions, and he
his opa hological ea u es o ARMD ha e also yielded
inconsis en esul s [8, 9, 12–19]. Ex a-a icula issues
e ie ed om pa ien s wi h ARMD a y conside ably in
hei his ologic p esen a ion. Mos o en issues display
p ominen mac ophage in il a ion as a esponse o he
cy o oxic me al wea deb is wi h a a iable amoun o
lymphocy ic in il a ion, ei he di use o agg ega ed
[2,3,8,13].Howe e ,inamino i yo pa ien swi h
ARMD, he e is hea y lymphocy ic in il a ion, esem-
bling ype IV hype sensi i i y eac ion [17, 20–23].
The p esence o lymphocy es is usually accompanied
wi h he p esence o nec osis and his ype o issue
esponse was i s e med ALVAL (Asep ic Lympho-
cy ic Vasculi is-Associa ed Lesion) by Wille e al.
[20]. Te ms ALVAL and ARMD ha e howe e been
inapp op ia ely used as synonyms in he ecen li e a u e
[24]. Low bea ing wea has been associa ed wi h a
suspec ed me al hype sensi i i y esponse in some s udies
[8, 9, 16]. Vice e sa, high bea ing wea has been associa ed
wi h a mac ophage-domina ed o eign-body esponse.
[8, 13]. In addi ion, low WB me al ion le els ha e
been associa ed wi h lymphocy e-domina ed issue
esponse and high me al ion le els wi h mac ophage-
domina ed esponse [17]. Based on hese indings, me al
hype sensi i i y o implan -de i ed deb is has been hypo h-
esized as a cause o ARMD in pa ien s wi h low-wea ing
hip implan s, and cy o oxic, mac ophage domina ed
esponse in pa ien s wi h high-wea ing hip implan s
[8, 13, 16, 17] Howe e , indings no suppo ing hese hy-
po heses ha e been published as well [10, 12, 15, 18, 19].
The his opa hology o ARMD has been well desc ibed
bu he li e a u e ega ding i s associa ion o implan
wea is inconsis en . I is impo an o unde s and he
ue na u e o he associa ion be ween wea and
his opa hological indings in ARMD. A e all, i is he
his opa hological changes – issue des uc ion and in-
lamma ion – ha lead o ailu e o MoM hip implan s.
Implan wea canno be measu ed in- i o and hus
canno be used in clinical decision making bu he e a e
eliable indi ec measu es o wea , such as WB me al ion
le els, ha a e commonly used in he ollow-up o
pa ien s wi h MoM hip eplacemen s. To gain a be e
unde s anding o he ela ionships be ween his opa ho-
logical indings, bea ing wea and clinical ma ke s o
wea we aimed o in es iga e bea ing su ace wea ol-
ume, WB and SF me al ion concen a ions as clinical
ma ke s o wea , and hei associa ions wi h his opa ho-
logical indings o he pe ip os he ic issue in pa ien s
wi h A icula Su ace Replacemen (ASR) hip
esu acing de ice e ised due o ARMD. Based on
hep e iousli e a u ewehypo hesized ha 1)low
implan wea is associa ed wi h high amoun o lym-
phocy es cha ac e is ic o an ALVAL esponse and 2)
high implan wea is associa ed wi h high amoun o
mac ophages cha ac e is ic o a o eign-body esponse
o me al wea deb is.
Me hods
Be ween he ecall o he ASR MoM hip sys em (Depuy
O hopaedics, Wa saw, IN, USA) in Augus 2010 and
he end o ou ec ui men pe iod in Janua y 2016, 114
ASR hip esu acing de ices in 107 pa ien s ha e been
e ised a ou ins i u ion. All consecu i ely e ised
pa ien s who ga e in o med consen and ul illed he
ollowing c i e ia we e included in ou s udy: 1) Re ision
was due o ARMD, 2) Re ie ed componen s we e a ail-
able o bea ing wea analysis and 3) Pe ip os he ic
issue sample was a ailable o his opa hologic analysis.
A e exclusion, 85 hips in 78 pa ien s we e included in
ou s udy. Twen y-one o hese pa ien s we e e e ed o
ou ins i u ion om cen al hospi als om o he hospi al
dis ic s and 57 pa ien s had had hei index ope a ion
(p ima y a h oplas y) and ollow-up a ou ins i u ion.
Su ge y was pe o med by o unde he di ec supe i-
sion o 14 senio o hopaedic su geons. The s udy was
app o ed by he e hical commi ee o Pi kanmaa
Hospi al Dis ic (R11006).
Re ision su ge y was conside ed i 1) a clea pseudo u-
mou (Impe ial class 2A,2B o 3) [25] was obse ed on
c oss-sec ional imaging ega dless o symp oms o WB
me al ion le els; o 2) he pa ien had ele a ed WB me al
ion le els and hip symp oms despi e no mal indings in
c oss-sec ional imaging; o 3) he pa ien had a con inu-
ously symp oma ic hip o p og essi e symp oms ega dless
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 2 o 11
o imaging indings o me al ion le els. Symp oms included
hip pain, discom o , sense o ins abili y, and/o impai ed
unc ion o he hip and sounds om he hip (clacking,
squeaking). WB me al ion le els we e ega ded as being
ele a ed i ei he ch omium o cobal exceeded 5 ppb. Pos -
ope a i ely, ailu e was classi ied as being due o ARMD on
he basis o he ollowing c i e ia [26, 27]: 1) he e was p es-
ence o me allosis o mac oscopic syno i is in he join ;
and/o 2) a pseudo umo was ound du ing e ision; and/
o 3) a mode a e o high numbe o pe i ascula lympho-
cy es along wi h issue nec osis and/o ib in deposi ion
was seen in he his opa hologic sample; and 4) pe iope a-
i ely he e was no e idence o componen loosening o
pe ip os he ic ac u e. In addi ion, in ec ion was uled ou
by ob aining mul iple (a leas i e) bac e ial cul u es du ing
e ision su ge y.
Bea ing wea analysis
The olume o ma e ial loss om he cup and head
bea ing su aces was measu ed using a Zeiss P ismo
(Ca l Zeiss L d., Rugby, UK) coo dina e measu ing
machine (CMM). A o al o 400 pola scan lines on each
su ace we e de ined and up o 30,000 da a poin s cap-
u ed using a 2 mm uby s ylus; p o ocols o his
me hod ha e been p e iously published [28]. An i e a i e
leas squa e i ing me hod was used o analyse he aw
da a cap u ed by he CMM and he unwo n geome y o
he bea ing su ace was used o map egions o ma e ial
loss om which he o al olume ic loss was calcula ed.
Wea a e (mm3/yea ) was u he calcula ed by di iding
o al wea olume in cubic millime e s by implan a ion
ime in yea s.
His opa hological analysis o he pe ip os he ic issue
Du ing e e y hip e ision, a sample o he in lamed
syno ia o pseudo umo was ob ained. Fo his opa ho-
logical analysis, each issue sample was o malin ixed.
Se e al 10 μm mic o ome sec ions we e made and em-
bedded in pa a in. S anda d hema oxylin and eosin
s aining was used. The sec ions we e examined his olog-
ically unde no mal ligh wi h a Nikon Eclipse 50i
(Nikon Co po a ion, Shinagawa, Tokyo, Japan). The
samples we e g aded by a senio musculoskele al pa h-
ologis (JP) using sco ing p inciples adop ed om he
s udy by Na u e al. [2] ( e med Na u g ading in ou
s udy) and he ALVAL sco e p e iously desc ibed by
Campbell e al. [8].
The Na u g ading consis ed o ollowing pa ame e s:
1) lymphocy e cu hickness, 2) whe he lymphocy ic in-
il a e was di use o agg ega ed, 3) p esence o ge mi-
nal cen e s, 4) his iocy e shee hickness, 5) me al
pa icle load wi hin his iocy es, 6) ex en o issue nec o-
sis, 7) p esence o plasma cells and 8) p esence o g anu-
lomas. Lymphocy e cu hickness was calcula ed using a
g a icule. An a e age o i e measu emen s was aken
and g aded as 0–3 (absen , 0.25 mm, 0.25–0.75 mm,
>0.75 mm). Thickness o his iocy e shee s was also cal-
cula ed using a g a icule and g aded 0–3 (absen ,
<1 mm, 1–2 mm, >2 mm). Me al pa icle load wi hin
his iocy es was g aded as 0–4 as done in he assessmen
o i on decomposi ion in li e cells [29, 30]. The ex en
o o e all issue nec osis in a sample was g aded based
on he su ace nec osis yping acco ding o Da ies e al.
[22]. Type 1 su ace con ains in ac syno ial epi helium.
Type 2 su ace shows loss o syno ial epi helial cells
wi hou ib in deposi ion. In ype 3 su ace he e is ib in
deposi ion and in ype 4 su ace he e is ex ensi e nec o-
sis and loss o a chi ec u e. The ex en o ype 4 su ace
nec osis was used o g ade he o e all issue nec osis in
a gi en sample, as desc ibed by Na u e al. [2]. In g ade
4 nec osis, mo e han 75% o he issue sample showed
ype 4 su ace nec osis. In g ade 3 nec osis, be ween 25
and 75% showed ype 4 su ace nec osis. In g ade 2 ne-
c osis ei he less han 25% o he issue showed ype 4
su ace nec osis o he issue showed ype 3 su ace. In
g ade 1 nec osis, he sample consis ed o ype 2 su ace.
ALVAL sco ing consis s o h ee subsco es: syno ial
lining (0-3p), issue o ganiza ion (0-3p) and in lamma-
o y in il a e (0-4p). Bo h syno ial lining and issue
o ganiza ion e lec he deg ee o nec osis and highe
sco es mean highe deg ee o nec osis. In lamma o y in-
il a e sco e e lec s he p edominan in lamma o y cell
ype on a spec um: 0 poin s means minimal in il a es,
1p means p edominan ly mac ophages, 2p means bo h
mac ophages and di use/pe i ascula lymphocy es, 3p
means mos ly lymphocy es in agg ega es and some mac-
ophages and 4p means la ge lymphocy e agg ega es and
li le o no mac ophages.
Whole blood and syno ial luid me al analysis
Since Janua y 2012, WB me al ion (Co and C ) con-
cen a ions ha e been ou inely measu ed as a pa o
he sys ema ic ollow-up p og am o pa ien s wi h
MoM hip eplacemen s a ou ins i u ion. All pa ien s
unde wen WB analysis o Co/C ollowing sampling
om he an ecubi al ein using a 21-gauge needle
connec ed o a Vacu aine sys em (Bec on, Dickinson
and Company, F anklin Lakes, NJ, USA) and ace-
elemen blood ubes con aining sodium e hylenedi-
amine e aace ic acid (EDTA). S anda d ope a ing
p ocedu es we e es ablished a he Finnish Ins i u e
o Occupa ional Heal h o Co and C measu emen
using dynamic eac ion cell induc i ely coupled
plasma (quad ipole) mass spec ome y (Agilen 7500
cx, Agilen Technologies, San a Cla a, CA, USA). The
labo a o y echnicians we e blinded o all clinical
ou comes. The samples we e p ese ed in +6 °C o
+8 °C p io o analysis.
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 3 o 11
Since Oc obe 2011, ou MoM hip e ision p o ocol
has in ol ed pe iope a i e SF aspi a ion, which is always
aken be o e opening he deep ascia using a s anda d
18- o 20-gauge needle connec ed o a Vacu aine sys em
(Bec on, Dickinson and Company, F anklin Lakes, New
Je sey) and ace elemen ubes con aining sodium
EDTA. Simila p ocedu es we e used o SF me al ion
concen a ion measu emen as desc ibed abo e o WB.
S a is ical me hods
Spea man ank co ela ion was used o s udy he associ-
a ions be ween wea olume, WB and SF me al ion
concen a ions, and his opa hological indings due o
non-no mal dis ibu ion o hese a iables. Medians
we e calcula ed o wea olume, WB and SF me al ion
concen a ions. To compa e hese median alues
be ween di e en subg oups, nonpa ame ic Mann-
Whi ney U- es was used. When analyzing he co el-
a ion be ween WB me al ion concen a ions and o he
ac o s, we only included pa ien s wi h unila e al hip
a h oplas ies (57 hips) o a oid he con ounding e ec
o me al ions being eleased o he blood om he o he
implan . The h eshold o s a is ical signi icance was se
o 0.05. The analyses we e conduc ed using IBM SPSS
so wa e (IBM Co p. Released 2012. IBM SPSS S a is ics
o Windows, Ve sion 21.0. A monk, NY: IBM Co p.).
Resul s
O he 85 hips included in he s udy, 56 we e explan ed
om emale pa ien s and 29 om male pa ien s. Mean
age a he ime o he e ision su ge y was 57.3 yea s
(SD 10.3 yea s). Mean ollow-up ime be ween index op-
e a ion and e ision su ge y was 5.4 yea s (SD 1.8 yea s).
Volume ic wea analysis o he explan ed componen s
demons a ed a wide ange o wea in bo h he ace abu-
la cup and emo al head (Table 1). Wea a es we e also
highly a iable wi h a median o 9.0 mm3/yea ( ange
1.1…99.7 mm3/yea ). In a as majo i y o he compo-
nen s (85.1%), he emo al head was mo e wo n han he
ace abula cup. Median a io o head wea o cup wea
was 1.7 ( ange, 0.5…10). In addi ion o ac ual olume ic
componen wea , also WB and SF me al ion le els, se -
ing as indi ec ma ke s o wea , we e highly a iable
(Table 2). The o al wea olume o he head and cup
s ongly co ela ed wi h WB me al ion concen a ions
(C : ρ= 0.80, p< 0.001 and Co: 0.84, p< 0.001) and
mode a ely wi h SF me al ion concen a ions (C : ρ=
0.50, p< 0.01 and Co: ρ= 0.41, p= 0.027). Wea a e had
sligh ly s onge co ela ion wi h WB me al ion concen-
a ions (C : ρ= 0.87, p< 0.001 and Co: 0.89, p< 0.001)
and SF me al ion concen a ions (C : ρ= 0.71, p< 0.001
and Co: 0.66, p< 0.01) han o al wea olume.
His ologically, a iable amoun s o mac ophages, lym-
phocy es and nec osis we e seen in he issue samples.
One o mo e ge minal cen e s we e p esen in 5 samples
(5.7% o all samples). One o mo e g anulomas we e
p esen in 14 samples (16.5% o all samples). All issue
samples e inced a leas some deg ee o mac ophage in-
il a ion (mac ophage shee hickness sco e o a leas
1) and in mos cases i was low o mode a e (Fig. 1). In
ega d o lymphocy e in il a ion, mos issues e inced
li le o no lymphocy es and in only a mino i y o he
samples he in il a e was p ominen (Fig. 2). All cases
wi h hea y lymphocy e in il a ion (sco es 2 o 3) had a
mac ophage shee hickness sco e o 1, ie. he e was only
li le mac ophage in il a ion in hese issues. Eigh o
he nine issue samples wi h hea y lymphocy e in il a-
ion had g ade 4 nec osis and he nin h had g ade 3 ne-
c osis. Median wea a e o hese issues was highe
han ha o he issues wi h lowe numbe s o lympho-
cy es (Table 3). Lymphocy e cu hickness co ela ed
posi i ely wi h he g ade o nec osis (ρ= 0.41, p< 0.001)
and in lamma o y in il a e sco e (ρ= 0.79, p< 0.001)..
All i e issue samples wi h ge minal cen e s had g ade 4
nec osis. The wea olume o wea a e o hese cases
did no di e om cases wi hou ge minal cen e s (me-
dian wea olume in cubic millime e s 61 e sus 37.5, p
= 0.94; median wea a e in cubic millime e s/yea 11.9
e sus 8.8, p= 0.86). Tissues wi h one o mo e g anu-
lomas we e associa ed wi h highe o al wea olume
and wea a e when compa ed o issues wi h no g anu-
lomas (Table 4). G ade o nec osis co ela ed posi i ely
wi h syno ial lining sco e (ρ= 0.86, p< 0.001) and issue
o ganiza ion sco e (ρ= 0.80, p< 0.001).
Co ela ions be ween his ological a iables, o al wea
olume o he head and cup componen s, wea a e as
well as WB and SF me al ion concen a ions a e lis ed in
Table 5. To al wea olume co ela ed wi h mac ophage
shee hickness, g ade o nec osis (Fig. 3), syno ial lining
sco e, issue o ganiza ion sco e and o al ALVAL sco e.
Wea a e had simila co ela ions bu he co ela ion
wi h mac ophages did no qui e each s a is ical signi i-
cance. WB cobal and ch omium ion concen a ions had
Table 1 Median olume ic wea and ange o ace abula and
emo al componen s and bo h combined
Componen Median olume ic wea (mm
3
) Range (mm
3
)
Ace abula cup 14 2–247
Femo al head 24 4–485
Bo h combined 39 7–541
Table 2 Median concen a ions (μg/l) and anges (μg/l) o
ch omium and cobal ions in bo h whole blood and syno ial luid
Me al ion Whole blood Range Syno ial luid Range
Ch omium 9.7 0.5–93.9 701 7.0–52360
Cobal 15.4 0.7–224.7 281.5 27.0–14870
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 4 o 11
Fig. 1 Dis ibu ion o mac ophage shee hickness sco es among all pe ip os he ic issue samples
Fig. 2 Dis ibu ion o lymphocy e cu hickness sco es among all pe ip os he ic issue samples
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 5 o 11

simila co ela ions. SF ch omium ion concen a ion
co ela ed wi h g ade o nec osis, syno ial lining sco e
and o al ALVAL sco e. SF cobal ion concen a ion co -
ela ed wi h all bu mac ophage shee hickness. Nei he
wea olume, wea a e, WB me al ion concen a ions o
SF ch omium ion concen a ion we e associa ed wi h
lymphocy e cu hickness o p esence o ge minal cen-
e s. Howe e , SF cobal ion concen a ion did co ela e
wi h lymphocy e cu hickness.
Discussion
In he p esen s udy, a spec um o in lamma o y and
nec o ic changes associa ed wi h ARMD we e seen –
a iable mac ophage and lymphocy e in il a ion and
nec osis in pe ip os he ic issues [2–4, 8, 21]. Mos
pa ien s e inced low- o-mode a e mac ophage in il a-
ion and li le o no lymphocy e in il a ion. A ew
pa ien s e inced a e y p ominen lymphocy e in il a-
ion wi h g ade 4 nec osis ypical o an ALVAL esponse
i s p oposed by Wille e al. [20]. The hickness o
lymphocy e cu s co ela ed posi i ely wi h he deg ee o
nec osis. Bea ing wea and WB me al ion concen a ions
co ela ed posi i ely wi h he numbe o mac ophages
and he deg ee o nec osis.
Ou s udy is no wi hou limi a ions. Fi s ly, due o he
pe ip os he ic issue being sampled only a he ime o
e ision su ge y, i is di icul o say abou he na u al
his o y o ARMD. Secondly, issue samples we e
analyzed by one obse e only. Howe e , mul iple mic o-
ome sec ions o each sample we e made and analyzed
by a senio musculoskele al pa hologis well acquain ed
wi h ARMD his opa hology. Thi dly, we did no pe o m
a p io i sample size calcula ion. Ou s udy was e o-
spec i e o na u e and pa ien s we e included on an
“all-come ”basis. Howe e , a pos e io i powe analysis
e ealed ha ou s udy has 90% powe (10% be a) o de-
ec 0.35 co ela ion (medium e ec size) wi h a ype I
e o p obabili y o 5% (al a). Fou hly, al hough we con-
secu i ely ec ui ed pa ien s, no all pa ien s who unde -
wen su ge y because o ARMD du ing he ec ui men
pe iod we e included due o e used consen , missing
issue samples and missing wea da a on some pa ien s.
Thus, ou pa ien se ies is no comple ely consecu i e.
Howe e , he numbe o excluded pa ien s was low in
compa ison o he numbe o consecu i e pa ien s in-
cluded. Indeed, he la ge numbe o pa ien s included is
a majo s eng h o ou s udy. Ano he s eng h is ha
we only included pa ien s e ised o ARMD and wi h
iden ical hip esu acing implan s. Thus, ou da a speci -
ically desc ibes pa ien s wi h ARMD while minimizing
he con ounding e ec om ha ing di e en implan
designs o ailu e modes o he han ARMD. Also, he e
was no con ounding e ec om possible unnion wea
deb is as in he case o THRs since we only in es iga ed
he e ec s o bea ing wea deb is.
Me al deb is o igina ing om he bea ing su aces
and/o unnion has been shown o ha e cy o oxic e -
ec s [31–34]. I has been sugges ed ha he cy o oxici y
o me al deb is u he leads o issue des uc ion and
mac ophage ec ui men o clea he issue and me al
deb is [3, 21]. In suppo o his, we obse ed a co el-
a ion be ween implan wea and he numbe o mac o-
phages as well as he deg ee o nec osis bu no wi h he
numbe o lymphocy es. Simila indings we e made in a
s udy by G amma opoulos e al. [13]. Lang on e al.
howe e did no ind co ela ion be ween wea and he
amoun o mac ophages o nec osis [6]. We also ob-
se ed ha he p esence o g anulomas was associa ed
wi h inc eased o al wea olume. G anulomas a e
hough o o m in esponse o high numbe o wea
pa icles and ou esul s suppo his idea [35]. High
wea , o high WB me al ion concen a ions, ha e been
associa ed o mac ophage-domina ed issue esponses in
o he s udies as well [8, 16, 17]. Me al hype sensi i i y
leading o ype IV esponse wi h s ong lymphocy ic in-
il a ion has been sugges ed as a cause o ailu e in
hose pa ien s wi h low wea [8, 16, 17]. Con a y o ou
hypo hesis, his was no obse ed in ou s udy. In ac ,
pa ien s wi h hea y lymphocy ic in il a ion had highe
wea a e han pa ien s wi h lowe numbe s o lympho-
cy es. These indings sugges ha excessi e me al deb is
accumula ion was he cause o lymphocy ic in il a ion
in hese pa ien s, no me al hype sensi i i y. G amma o-
poulos e al. also did no ind co ela ion be ween wea
and lymphocy ic in il a ion, bu no ed he p esence o a
pa ien subg oup wi h hype sensi i i y- ela ed his o-
pa hological indings and simul aneous low bea ing wea ,
sugges ing me al hype sensi i i y as a cause o ailu e in
hose pa ien s [13].
Table 3 Wea a es acco ding o lymphocy e cu hickness
Lymphocy e
cu <2
Lymphocy e
cu 2 o 3
P- alue
Median wea a e (mm3/yea ) 8.1 14.5 0.054
Range (mm3/yea ) 1.1 …99.8 3.7 …48.0
Table 4 Wea olume and a e: compa ison be ween pa ien s
wi h one o mo e g anulomas and hose wi hou g anulomas
G anuloma p esen G anuloma absen P- alue
Median o al wea
olume (mm3)
106.5 31.0 0.016
Range (mm3) 10…378 7…541
Median wea a e
(mm3/yea )
16.3 8.1 0.035
Range (mm3/yea ) 1.6…99.8 1.1…86.4
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 6 o 11
The e a e se e al easons ha likely con ibu e o he
inconsis ency o indings be ween di e en his opa ho-
logical s udies. I is possible and p obable ha some pa-
ien s ha e bo h high-wea ing implan s and an
unde lying hype sensi i i y esponse ha would ha e
e oked e en in he p esence o a low-wea ing implan .
This combina ion may esul in a mixed- ype issue e-
sponse ha has he cha ac e is ics o bo h wea - ela ed
o eign-body esponse and hype sensi i i y- ela ed ype
IV issue esponses and he e o e makes i di icul o
dis inguish be ween he wo based on implan wea o
WB me al ion le els alone. Also, h eshold o he onse
o adap i e immune esponse is likely a iable be ween
indi iduals [13]. This would explain why some pa ien s
ole a e ex ensi e amoun o wea deb is and some pa-
ien s de elop ALVAL in he p esence o a low wea ing
MoM hip eplacemen . In addi ion o pa ien suscep i-
bili y, di e ences in implan ypes among s udies may
Table 5 Spea man ho co ela ion coe icien s and associa ed p- alues o co ela ions be ween o al wea olume, wea a e,
indi ec ma ke s o wea (whole blood and syno ial luid me al ion concen a ions) and his opa hological g ading (Na u and ALVAL)
Na u g ading ALVAL g ading
Lymphocy ic
cu ing
Mac ophage
shee hickness
G ade o
nec osis
In lamma o y
in il a e sco e
Syno ial lining
sco e
Tissue o ganiza ion
sco e
To al ALVAL
sco e
To al wea olume ho = 0.11
p= 0.32
ho = 0.25*
p= 0.020
ho = 0.35*
p< 0.01
ho = 0.13
p= 0.23
ho = 0.37*
p< 0.01
ho = 0.25*
p= 0.023
ho = 0.31*
p< 0.01
Wea a e ho = 0.17
p= 0.12
ho = 0.20
p= 0.069
ho = 0.42*
p< 0.0001
ho = 0.16
p= 0.15
ho = 0.48*
p< 0.0001
ho = 0.35*
p< 0.01
ho = 0.40*
p< 0.001
WB C ho = 0.089
p= 0.51
ho = 0.30*
p= 0.024
ho = 0.45*
p< 0.001
ho = 0.19
p= 0.26
ho = 0.54*
p< 0.001
ho = 0.33*
p= 0.015
ho = 0.48*
p< 0.001
WB Co ho = 0.18
p= 0.18
ho = 0.29*
p= 0.029
ho = 0.51*
p< 0.001
ho = 0.26
p= 0.055
ho = 0.60*
p< 0.001
ho = 0.40*
p< 0.01
ho = 0.55*
p< 0.001
SF C ho = 0.30
p= 0.12
ho = 0.16
p= 0.40
ho = 0.48*
p< 0.01
ho = 0.25
p= 0.19
ho = 0.56*
p< 0.01
ho = 0.34
p= 0.070
ho = 0.53*
p< 0.01
SF Co ho = 0.49*
p< 0.01
ho = 0.17
p= 0.37
ho = 0.54*
p< 0.01
ho = 0.44*
p= 0.017
ho = 0.47*
p= 0.011
ho = 0.38*
p= 0.045
ho = 0.57*
p< 0.01
Values ha a e s a is ically signi ican a e lagged wi h *
Fig. 3 The di e ence in median o al wea olume (head and cup) in pa ien s wi h low-g ade nec osis (g ades 1 and 2) e sus pa ien s wi h
high-g ade nec osis (g ades 3 and 4), p< 0,001
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 7 o 11
play a ole. Subs an ially highe ailu e a es ha e been
epo ed o ASR XL THRs in compa ison wi h ASR hip
esu acings [5, 19]. ASR XL and ASR ha e simila
bea ing couples, bu in he ASR XL he e is unnion-
in e ace be ween he i anium s em and CoC head ha
se es as an addi ional sou ce o me al deb is. I has
been shown ha wea om he unnion is di e en
in na u e compa ed o bea ing su ace wea and may
lead o lymphocy ic and nec o ic issue esponses
[14, 36, 37], possibly con ibu ing o he inconsis en-
cies be ween o he ecen his opa hological s udies.
Na u e al. sugges ed ha he lymphocy ic immune e-
sponse in pa ien s wi h MoM implan s is a dynamic
p ocess, beginning wi h pe i ascula lymphocy ic agg e-
ga es and leading o o ma ion o lymphoid ollicles wi h
ge minal cen e s, also e med as e ia y lymphoid o -
gans (TLOs) [2]. TLOs a e capable o o ming new B
and T cells locally. TLOs a e seen in a ec ed issues o pa-
ien s wi h ch onic au oin lamma o y diseases such as
heuma oid a h i is, Sjog ens synd ome and Hashimo o’s
hy oidi is and a e conside ed o be o med as a esponse
o a pe sis en an igen ha canno be elimina ed [38].
Mi al e al. demons a ed he p esence o TLOs and asso-
cia ed chemokines in issues o pa ien s wi h ailed MoM
hip implan s and sugges ed ha hese pa ien s o m a
speci ic pa hological subse [39] in addi ion o he well-
es ablished o eign-body esponse [3, 13] and ALVAL e-
sponse [8, 20, 40]. In keeping wi h indings by Na u e al.
and Mi al e al., we ound ha a mino i y o he pa ien s
displayed lymphoid ollicles wi h ge minal cen e s. Fu -
he , all issue samples displaying ge minal cen e s had
g ade 4 nec osis. This sugges s ha he o ma ion o
TLOs in pe ip os he ic issues is associa ed wi h issue de-
s uc ion, possibly accele a ing he p ocess o implan ail-
u e. In line wi h his is a inding ha he p esence o
TLOs has been associa ed wi h issue des uc ion and loss
o unc ion in au oimmune diseases [38]. In he p esen
s udy, we also obse ed ha e en in he absence o ge mi-
nal cen e con aining lymphoid ollicles, he hickness o
lymphocy ic cu s co ela ed wi h he g ade o nec osis.
Whe he he lymphocy ic immune esponse, also e med
ALVAL, is a dynamic p ocess leading o o ma ion o
TLOs as Na u e al. sugges ed [2] o whe he pa ien s wi h
TLOs de ine hei own dis inc pa hological subse as Mi -
al e al. sugges ed [39] equi es u he esea ch. Howe e ,
due o he c oss-sec ional na u e o his opa hological
s udies, i is di icul o in es iga e he na u al his o y o
ARMD.
ALVAL g ading in oduced by Campbell e al. [8] has
been used in se e al s udies [9, 16, 18, 41] bu o he g ad-
ing sys ems ha e been used as well [2, 13, 21, 22, 36]. This
makes compa ison be ween s udies di icul . In he
p esen s udy, all issue samples we e analyzed acco ding
o wo g ading c i e ia: ALVAL g ading and g ading
p inciples es ablished by Na u e al. [2]. ALVAL g ading is
ela i ely es ic ed compa ed o he Na u g ading as i
only includes in lamma o y in il a e sco e, syno ial lining
sco e and issue o ganiza ion sco e. Mo eo e , as dis-
cussed by Riccia di e al., bo h syno ial lining sco e and
issue o ganiza ion sco e e lec he deg ee o nec osis
[21]. A s ong co ela ion be ween hese sco es and he
Na u sco e o nec osis was obse ed in ou s udy. ALVAL
sco e was o iginally designed o help dis inguish ailu es
ela ed o high wea om ailu es ela ed o suspec ed
hype sensi i i y (ALVAL) esponse. Al hough nec osis is
o en seen wi h ALVAL esponse, i is no speci ic o
ALVAL as i is also seen wi h mac ophage-domina ed
o eign body eac ions wi h possible ela ed cy o oxici y
[3, 13]. This lea es only he in lamma o y in il a e sco e
in ALVAL g ading speci ic o ALVAL esponse. In he
p esen s udy, a s ong co ela ion be ween lymphocy e
cu hickness and in lamma o y in il a e sco e was ob-
se ed. This indica es ha he in lamma o y in il a e
sco e is use ul in dis inguishing lymphocy e-domina ed e-
sponses om hose ha a e no lymphocy e-domina ed.
Phillips e al. also concluded ha ALVAL sco ing is use ul
o dis inguishing be ween mac ophage and lymphocy e
esponses [42]. In lamma o y in il a e sco e in ol es
e alua ion o bo h lymphocy ic and mac ophagic compo-
nen s. Howe e , bo h lymphocy es and mac ophages a e
o en seen in pe ip os he ic issues. G amma opoulos e
al. sugges ed ha an easie me hod o iden i y ALVAL e-
sponses om wea - ela ed esponses would be o measu e
only he hickness o lymphocy ic cu ing, e med Ox o d-
ALVAL sco e in hei s udy [13]. We ag ee wi h G amma-
opoulos e al. and ind ha sepa a e sco es o e alu-
a ion o mac ophage and lymphocy e in il a ion
p o ide mo e in o ma ion abou he ailu e mechan-
ism and lead o easie compa ison be ween his o-
pa hological s udies.
In he p esen s udy, WB me al ion le els had a s ong
co ela ion wi h bea ing wea olume, wea a e and a
mode a e co ela ion wi h se e al his opa hological
ea u es. SF me al ion le els also co ela ed wi h bea ing
wea olume, wea a e and some o he his opa ho-
logical ea u es, bu he co ela ions we e weake . Wea
a e had a s onge co ela ion wi h WB and SF me al
ion le els han o al bea ing olume. Wea a e, WB and
SF me al ion le els likely e lec he ecen bu den o
me al deb is whe eas o al wea olume e lec s he
amoun o o al wea accumula ed du ing implan a ion
ime. In a s udy by De Sme e al. bo h WB and SF me al
ion le els we e ound o co ela e well wi h linea wea
o he emo al componen [43]. Lang on e al. also no ed
a co ela ion be ween wea olume and WB me al ion
le els [6]. In e es ingly, WB me al ion le els had s on-
ge co ela ion wi h his opa hological indings compa ed
o SF me al ion le els in he p esen s udy. This is
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 8 o 11
suppo ed by a ecen s udy by Rei o e al. who ound
ha SF me al ion le els had ela i ely poo co ela ion
wi h his opa hological indings [12]. SF aspi a ion is an
in asi e p ocedu e and he measu emen does no seem
o p o ide any addi ional in o ma ion compa ed o WB
measu emen . Measu emen o WB me al ion le els is a
eliable, indi ec way o gain in o ma ion o he in-si u
wea p ocess, in lamma ion and issue des uc ion. Clini-
cians should use WB me al ion le els in he ollow-up o
pa ien s wi h MoM hip implan s and closely moni o
hose pa ien s wi h ele a ed me al ion le els. A
schema ic diag am o he ela ionships be ween wea ,
his ology o he pe ip os he ic issues, WB me al ion le els
and ollow-up o he pa ien s is p esen ed in Fig. 4.
Conclusions
In he p esen s udy wi h ailed ASR hip esu acings,
o al wea olume, wea a e and WB me al ion concen-
a ions co ela ed wi h he numbe o mac ophages and
he deg ee o nec osis, bu no wi h he amoun o lym-
phocy es. Mos issue samples e inced mac ophages bu
li le o no lymphocy es ypical o a non-speci ic o eign-
body esponse. A mino i y o he samples e inced s ong
lymphocy e in il a ion combined wi h high amoun o
nec osis, ypical o an ALVAL esponse. Howe e ,
con a y o ou hypo hesis, his ype o esponse was no
associa ed wi h low implan wea in he p esen s udy.
The signi icance o pa ien suscep ibili y in he de elop-
men o ARMD is poo ly unde s ood and i is no
cu en ly known which ac o s lead o he adap i e
lymphocy ic esponse seen in some pa ien s. Fu u e
s udies should be di ec ed o unde s and he pa ho-
physiological mechanisms behind di e en ypes o
issue esponses seen in pa ien s wi h MoM hips. WB
me al ion le els co ela ed wi h o al wea olume,
wea a e and his opa hological indings. Measu e-
men o WB me al ion le els is use ul in he ollow-
up o pa ien s wi h hip esu acings as i p o ides
in o ma ion o he wea p ocess, in lamma o y e-
sponse and issue des uc ion.
Abb e ia ions
ALVAL: Asep ic lymphocy ic asculi is-associa ed lesion; ARMD: Ad e se eac ion
o me al deb is; ASR: A icula su ace eplacemen ; CoC: Ce amic-on-ce amic;
MoM: Me al-on-me al; MoP: Me al-on-polye hylene; SF: Syno ial luid; THR: To al
hip eplacemen ; TLO: Te ia y lymphoid o gan; WB: Whole blood
Acknowledgemen s
We wish o hank Ms. Ella Leh o o main aining ou s udy da abase.
Funding
The s udy was suppo ed by he compe i i e esea ch unds o Pi kanmaa
Hospi al Dis ic , Tampe e, Finland (g an 9 N044, ep esen ing go e nmen
unding). The sou ce o unding had no ole a any s age o his s udy.
A ailabili y o da a and ma e ials
The da ase s gene a ed and/o analysed du ing he cu en s udy a e no
publicly a ailable due o indi idual p i acy o he pa ien s. Da a may be
a ailable upon eques by email o he i s au ho .
Au ho s’con ibu ions
LL o med and analyzed he da a and w o e he ini ial d a o he manusc ip .
AR, JP, HH, AH, JH and AE assis ed in in e p e a ion o he da a and edi ing he
manusc ip . All au ho s ead and app o ed he inal manusc ip .
E hics app o al and consen o pa icipa e
All pa ien s ga e in o med consen and he s udy was app o ed by he
e hical commi ee o Pi kanmaa Hospi al Dis ic (R11006).
Consen o publica ion
No applicable.
Fig. 4 A schema ic diag am o he ela ionships be ween wea , his ology o he pe ip os he ic issues, whole blood me al ion le els and
ollow-up o he pa ien s
Leh o i a e al. BMC Musculoskele al Diso de s (2017) 18:523 Page 9 o 11